2-28529405-T-C

Position:

• chr2-28529405-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_153021.5(PLB1):​c.414T>C​(p.Ala138=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000917 in 1,594,000 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00078 (6 hom.)
• Consequence: PLB1 NM_153021.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002612
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.369

Genes affected

PLB1 (HGNC:30041): (phospholipase B1) This gene encodes a membrane-associated phospholipase that displays lysophospholipase and phospholipase A2 activities through removal of sn-1 and sn-2 fatty acids of glycerophospholipids. In addition, it displays lipase and retinyl ester hydrolase activities. The encoded protein is highly conserved and is composed of a large, glycosylated extracellular domain composed of four tandem homologous domains, followed by a hydrophobic segment that anchors the enzyme to the membrane and a short C-terminal cytoplasmic tail. This gene has been identified as a candidate rheumatoid arthritis risk gene. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-28529405-T-C is Benign according to our data. Variant chr2-28529405-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 728995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.369 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLB1	NM_153021.5	c.414T>C	p.Ala138=	splice_region_variant, synonymous_variant	7/58	ENST00000327757.10
PLB1	NM_001170585.2	c.414T>C	p.Ala138=	splice_region_variant, synonymous_variant	7/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLB1	ENST00000327757.10	c.414T>C	p.Ala138=	splice_region_variant, synonymous_variant	7/58	1	NM_153021.5	P1
PLB1	ENST00000422425.6	c.414T>C	p.Ala138=	splice_region_variant, synonymous_variant	7/57	1
PLB1	ENST00000404858.5	c.411T>C	p.Ala137=	splice_region_variant, synonymous_variant	7/57	1
PLB1	ENST00000416713.5	c.246T>C	p.Ala82=	splice_region_variant, synonymous_variant	7/11	5

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00117 AC: 294 AN: 251338 Hom.: 1 AF XY: 0.00113 AC XY: 153 AN XY: 135856

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000792

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000780 AC: 1125 AN: 1441690 Hom.: 6 Cov.: 30 AF XY: 0.000782 AC XY: 562 AN XY: 718456

Gnomad4 AFR exome AF: 0.00479

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.000845

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000699

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000630

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152310 Hom.: 0 Cov.: 31 AF XY: 0.00231 AC XY: 172 AN XY: 74482

Gnomad4 AFR AF: 0.00539

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PLB1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.98
DANN	Benign	0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144640748; hg19: chr2-28752272;